Intravenous gamma globulin (IVIG) is a remarkably safe and effective therapy for a number of autoimmune diseases. Recent studies indicate that the binding of Ig Fc to the neonatal Fc receptor determines the half-life of antibodies in vivo. In addition, the relative binding to Fc gamma RIll and RIIB may contribute to the protective effect of IVIG. Based on these observations we hypothesize that novel genetically engineered Fc regions of IgG antibodies (FcGam) designed to differentially bind to the Fc receptors in vivo can be used as improved, alternative therapeutics to IVIG. To test this concept, we propose to produce and test several novel Fc receptor-modulating proteins. In phase I the FcGams will be produced using our mammalian expression system, purified and compared for their capacity to modulate Fc receptor function. Based on a successful outcome of these experiments, the best FcGam will be selected for Phase II studies. Phase II will support preclinical animal models of autoimmunity, scale-up production and submission of an IND.